Self-injurious behavior (SIB) is a devastating disorder that is common in intellectually handicapped populations. We propose to use an animal model of SIB, the pemoline model, to examine the neurobiological mechanisms which underlie SIB. Pemoline is an indirect monoamine agonist, which blocks the reuptake of monoamines by their respective transporters. Consequently, a thorough characterization of pemoline's effects on the brain will take collaborative efforts from our entire laboratory. This proposal focuses on the effects of pemoline on presynaptic dopaminergic neurons in areas of the midbrain and forebrain. We have recently identified that rats treated repeatedly with pemoline have reduced intracellular dopamine concentrations. In this application we propose to examine the regional expression and functional activation of two of the most important regulators of dopaminergic neurotransmission, tyrosine hydroxylase (TH) and the dopamine transporter (DAT). We will use in situ hybridization to assay the regional expression of TH and DAT and western blots and autoradiography to measure the functional activation of the TH and DAT proteins, respectively. Because rats differ in their vulnerability to develop pemoline-induced SIB, we will compare the regional expression and functional activation of TH and DAT between pemoline-treated self-injurious, pemoline-treated non-injurious and vehicle-treated rats. This information may guide future studies investigating the neurobiological mechanisms which lead a subset of people with particular developmental disorders (e.g. autism, Lesch-Nyhan, Prader-Willi and Rett syndromes) to self-injure. These projects may also reveal new targets for SIB pharmacotherapies. PUBLIC HEALTH RELEVANCE: Self-injury, a behavioral trait of numerous developmental disorders, can lead to permanent tissue damage or tissue loss. Self-injury interrupts socialization and cognitive development and the self-injurers require specialized care and professional interventions (e.g. behavior modification therapy). These proposed projects will begin to elucidate some of the neurobiological mechanisms that lead to the expression of self-injury and may lead to the development of new pharmacotherapies...